Iontophoretic drug delivery

ABSTRACT

Improved methods of ionophoretic drug delivery are described. By the intentional selection of drug(s) with specific characteristics, of ionotophoresis device, components or both permits the efficiency of drug delivery is increased.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of copending application Ser. Nos.07/665,698 filed on Oct. 29, 1984 and 07/665,699 filed on Oct. 29, 1984,now issued as U.S. Pat. Nos. 4,474,819 and 4,744,787.

BACKGROUND OF THE INVENTION

This invention relates to methods and apparatus for transdermalmedicament delivery and to improvements therein. More specifically, thisinvention relates to improved methods and apparatus for active (asopposed to passive) transdermal, ambulatory, drug delivery. Yet moreparticularly, this invention relates to increased efficiencyiontophoresis devices or appliances and to improved methods of makingand using such devices.

Iontophoresis, according to Dorland's Illustrated Medical Dictionary, isdefined to be "the introduction, by means of electric current, of ionsof soluble salts into the tissues of the body for therapeutic purposes."Iontophoretic devices have been known since the early 1900's. Britishpatent specification 410,009 (1934) describes an iontophoric devicewhich overcame one of the disadvantages of such early devices known tothe art at that time, namely the requirement of a special low tension(low voltage) source of current which meant that the patient needed tobe immobilized near such source. The device of that Britishspecification was made by forming from the electrodes and the materialcontaining the medicament or drug to be delivered transdermally, agalvanic cell which itself produced the current necessary foriontophoretically delivering the medicament. This ambulatory device thuspermitted iontophoretic drug delivery with substantially lessinterference with the patient's daily occupation.

More recently, a number of United States patents have issued in theiontophoresis technology, indicating a renewed interest in this mode ofdrug delivery. For example, U.S. Pat. No. 3,991,755 issued to Jack A.Vernon et al; U.S. Pat. No. 4,141,359 issued to Stephen C. Jacobson etal; U.S. Pat. No. 4,398,545 issued to Wilson; U.S. Pat. No. 4,250,878issued to Jacobsen disclose examples of iontophoretic devices and someapplications thereof. The iontophoresis process has been found to beuseful in the transdermal administration or introduction of medicamentsor drugs including lidocaine hydrochloride, hydrocortisone, acetic acid,fluoride, penicillin, dexamethasone sodium phosphate and many otherdrugs. Perhaps the widest use of iontophoresis is that of diagnosingcystic fibrosis by using pilocarpine nitrate iontophoresis. Thepilocarpine nitrate stimulates sweat production; the sweat is collectedand analyzed for its chloride content to detect the presence of thedisease.

In presently known iontophoretic devices, at least two electrodes aregenerally used. Both these electrodes are disposed so as to be inintimate electrical contact with some portion of the skin of the body.One electrode, called the active electrode, is the electrode from whichthe ionic substance, medicament, drug precursor or drug is delivered ordriven into the body by electrical repulsion. The other electrode,called the indifferent or ground electrode, serves to close theelectrical circuit through the body. In conjunction with the patient'sskin contacted by the electrodes, the circuit is completed by connectionof the electrodes to a source of electrical energy, e.g., a battery, orappropriately modified household current. For example, if the ionicsubstance to be driven into the body is positively charged, then thepositive electrode (the anode) will be the active electrode and thenegative electrode (the cathode) will serve to complete the circuit. Ifthe ionic substance to be delivered is negatively charged, then thenegative electrode will be the active electrode and the positiveelectrode will be the indifferent electrode.

Furthermore, existing iontophoresis devices generally require areservoir or source of the ionized or ionizable species (or a precursorof such species) which is to be iontophoretically delivered orintroduced into the body. Examples of such reservoirs or sources ofionized or ionizable species include a pouch as described in thepreviously mentioned Jacobsen U.S. Pat. No. 4,250,878, or the pre-formedgel body of U.S. Pat. No. 4,383,529 issued to Webster. Such drugreservoirs, when electrically connected to the anode or the cathode ofan iontophoresis device to provide a fixed or renewable source of one ormore desired species, are generally used with anodes or cathodes whichare substantially electrochemically inert. As is more fully discussedbelow, utilization of such substantially inert electrodes ascontemplated in the prior art has significant disadvantages.

The present invention provides enhanced methods and apparatus for theiontophoretic delivery of ionized or ionizable medicaments e.g., drugs,by means of the intentional selection and utilization of a combinationof anode or cathode conductive members or electrodes having specifiedcharacteristics and the drug(s) to be delivered. Use of this inventionincreases the efficiency, safety and acceptability of the iontophoreticdrug delivery process.

BRIEF SUMMARY OF THE INVENTION

Briefly, in one aspect, the present invention is a method ofiontophoretic drug delivery wherein the drug to be iontophoreticallydelivered, an electrochemically active component of the drug deliveryapparatus, or both, are intentionally selected so that during operationof the device, the production of unwanted species is minimized. Inanother aspect of this invention, the drug to be iontophoreticallydelivered, an electrochemically active component of the apparatus orboth are intentionally selected to reduce the formation of unwantedwater hydrolysis products during operation of the device. In yet anotheraspect of this invention, the drug to be delivered, an electrochemicallyactive component of the iontophoresis apparatus or both, areintentionally selected so as to reduce the presence of water hydrolysisproducts after they are formed. As contemplated herein, anelectrochemically active component of an iontophoresis device is a partof the device which is oxidized or reduced during iontophoretic drugdelivery or which oxidizes or reduces other available species.

The present invention also contemplates improved bioelectrodesparticularly suited for use with iontophoresis device or appliance. Theimproved electrode of this invention provides an iontophoretic devicewhich exhibits enhanced coulombic efficiency in drug delivery processes.The electrode comprises a reservoir containing the medicament to beiontophoretically delivered, the reservoir being in electricalconnection with an electrochemically active component, e.g., an activecurrent distribution member, the species produced from theelectrochemically active component during operation of the deviceinteracting with the counterion of the medicament of the reservoirduring iontophoretic drug delivery so as to minimize the formation anddelivery of undesired species, the electrochemically active componentbeing in further electrical connection with a source of electricalenergy. In a preferred aspect, the electrode includes means to securethe electrode to the skin so as to permit iontophoretic drug deliverytherefrom.

In a further aspect, the present invention is a method of iontophoreticdrug delivery having enhanced coulombic efficiency comprising the stepsof selecting the ionic species e.g., a drug, to be iontophoreticallydelivered; incorporating the ionic species into an electrode such as inits medicament reservoir; selecting the composition or construction ofeither the anode or the cathode of the iontophoresis device to includean electrochemically active component so that electrochemical reactionat the anode or the cathode produces species which interact with theionic species so as to reduce the formation of undesired ions; placingthe selected anode or cathode in electrical connection with the ionicspecies (e.g., in connection with the reservoir) and with a source ofelectrical energy; and transdermally delivering the selected ionicspecies into the body while minimizing the formation and delivery ofundesired species.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a first iontophoresis electrodeaccording to the present invention.

FIG. 2 is a cross-sectional view of a second iontophoresis electrodeaccording to the present invention.

FIG. 3 is a lower, plan view of the iontophoresis electrode of FIG. 2.

FIG. 4 is a cross-sectional view of a third iontophoresis electrodeaccording to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The genesis of this invention was in the realization that knowniontophoretic drug delivery processes have an efficiency in the range ofabout 5% or less and that iontophoretic drug delivery is largely adiffusion dependent process. This means that approximately 95% of thecurrent utilized in known iontophoresis processes is consumed inactivities other than delivering the intended drug. For example, muchcurrent is wasted by the migration of highly mobile species such as H⁺,OH⁻, →Na⁺ and C1⁻.

Thus it was realized that iontophoretic drug delivery efficiency wouldbe enhanced if the availability of species which are more mobile thanthe drug which was to be delivered were minimized. Minimization of theconcentration or charge of species which were more easily transportedthan the intended species (i.e., a drug) is utilized herein to provideenhanced drug delivery. It is the enhanced drug delivery describedherein which may permit iontophoresis to become a viable alternative toother drug delivery techniques.

Prior art iontophoretic devices often utilize substantially inertstainless steel, nickel or other nickel and iron alloys as currentdistribution members or electrodes. During operation of suchiontophoretic devices in accordance with prior art iontophoretic drugdelivery methods, electrolysis of water occurs. Hydronium (H⁺) ions areformed at the anode and hydroxide ions (OH⁻) are produced at thecathode. In addition, gaseous hydrogen and oxygen are evolved at thecathode and anode, respectively. (Use of nickel or nickel-containingalloys e.g., stainless steel, also occasionally results in the formationof nickel ions at the anode. The nickel ions are then free to migrateinto the drug reservoir of the device and from there into the body.)

Iontophoretic devices which employ such essentially inert electrodeshave several inherent disadvantages. First, they exhibit reducedcoulombic efficiency of drug transfer (i.e. of charge species) due tothe formation of highly mobile hydronium and hydroxyl ions at theelectrodes. In addition, such devices evidence instability of pH in theanodic and cathodic reservoirs and adjacent the skin due to theformation of hydronium or hydroxyl ions and gaseous products (hydrogenand oxygen) at the electrodes. Lastly, as noted above, while prior artiontophoretic electrodes are substantially electrochemically inert someundesirable oxidation of e.g., nickel or other alloy metals, does occur.

These disadvantages mean that known iontophoretic devices used accordingto conventional drug delivery methods have the following drawbacks:

1) Lower coulombic efficiency requires that the battery for a portableor ambulatory device be larger (i.e. of higher capacity). In addition,the voltage required to maintain a certain therapeutic dose rate becomeslarger as the coulombic efficiency becomes smaller.

2) The shift in pH in the cathodic and anodic reservoirs, caused by theelectrolysis of water, can cause skin irritation, possible degradationthe physical properties of the gel components of the device or changethe activity of the drug.

3) The formation of hydrogen and oxygen gas at the electrodes can resultin a loss of contact between the electrodes and reservoirs leading toreduced device performance.

4) The oxidation of nickel or other metals at the anode results in thecontamination of the anodic reservoir with metal ions which then arefree to migrate into the skin and body with possible deleteriouseffects.

It is to overcome these disadvantages and increase the overallefficiency of the iontophoresis process that the present invention wasmade.

One method contemplated by the present invention for reducing theformation of undesirable or undesired hydronium ions at an electrode andto reduce contamination of the drug reservoir due to the oxidation ofelectrode metal is to intentionally select an electrode (e.g., an anode)comprising an electrochemically active or sacrificial component which,when oxidized or reduced during operation of the device, produces aspecies which immediately reacts with ions (e.g., anions) present in theelectrode or available to the electrode e.g., in the drug reservoir(which also may be selected, to form an insoluble salt or neutralchemical compound, e.g. H₂ O. "Sacrificial" as that term is used hereinmeans that at least a portion of the electrode (whether anode orcathode) is electrochemically oxidized or reduced during transdermaldrug delivery. "Electrochemically active", as the term is used herein,means "sacrificial" as defined above, but includes a material that isnot itself oxidized or reduced but which participates inoxidation/reduction. The anion or cation present in the drug reservoircan be present as a separately added material or as the counter-ion toan anionic or cationic drug to be delivered. Illustrating this practiceof the invention, the chloride (or hydrochloride) form of a positivelycharged drug (D⁺) would be chosen to be delivered (e.g., by adding it tothe reservoir) and the anode would have a silver electrochemicallyactive component which would be sacrificed by oxidation duringiontophoresis. The electrochemically generated silver ions would reactwith the chloride ion in the drug reservoir to form silver chloride.Thus, it is seen that the design of the sacrificial or electrochemicallyactive component of electrode/drug reservoir system can require theselection of an appropriate electrode material, or electrodeconstruction, drug, drug salt or both.

By this expedient, i.e., precipitation of an insoluble species, silverions and chloride ions are removed from the drug delivery systems andthus are not available to migrate through the reservoir and into thebody and therefore the device is more efficient, requiring less batteryenergy to deliver the drug. The efficiency of delivery of desiredspecies is increased because unwanted species such as Ag⁺ and C1⁻ aresimply removed from the system. Furthermore, production of H⁺ isminimized or avoided thus minimizing pH variation and O₂ production.

In an analogous fashion, if a neutral species is formed from undesiredions (rather than one which precipitates from the system) there is againa net removal of unwanted species since neutral species also would notreduce the efficiency of delivery of charged drug species by migratingin response to electrical currents.

Possible electrode electrochemically active component materials and druganions for sacrificial electrode devices are numerous, but in general,silver, copper and molybednum metals form insoluble halide salts (e.g.AgC1, AgI, AgBr, CuC1, CuI, CuBr, MoCl₃, MoI₂) and therefore arepossible sacrificial anode candidates for delivery of cationic drugs. Inaddition, ferro and ferricyanides of many metals (e.g., Ag, Sn, Zn, Ni,Mn) are insoluble and therefore combination of these metals with ironcyanide doped reservoirs may provide suitable sacrificial anode/drugreservoir systems. Additional electrodes employing sacrificial anodeswould include electrodes having a tin or zinc anode and in whichphosphate ions were the counterions to the cationic drug, electrodeshaving zinc anodes and having oxalate ions as the counterion to thecationic drug and electrodes having copper anodes and citrate ions asthe counterions to the cationic drug. As noted above, preferentially,the drug will be compounded with its counterion.

The silver anode/drug chloride sacrificial system is particularlypreferred for two reasons. First, silver chloride is highly insolubleand second, many catonic drugs can be purchased in the hydrochlorideform which means that the chloride anion in the drug reservoir will bepresent as the counterion to the drug cation. During operation of aniontophoretic device with a silver anode (e.g., a silver currentdistribution member) and chloride-containing reservoir, silver isoxidized (Ag→Ag⁺ +e⁻) and then reacts with the chloride ion to forminsoluble silver chloride near the surface of the silver anode (Ag⁺ +C1⁻→AgC1). Simultaneously, the drug cation migrates from the reservoir intothe body with greater efficiency than if the oxidation of water to formhydronium ion were allowed to occur at the anode if the anode weresubstantially inert i.e., it had no electrochemically active component.

An example of a system where the anion in the drug reservoir is presentas an additive is the copper/potassium ferrocyanide system. When K₃Fe(CN)₆ is added to the drug reservoir, FeCN₆ ³⁻ anions are formed. Byplacing the drug reservoirs in contact with e.g., a copper anode, theinsoluble salt, Cu₃ Fe(CN)₆ will be formed during device operation.However, unlike the silver/chloride system where the drug cationmigrates into the body, in this sytem, potassium ions will be free tomigrate from the drug reservoir into the body. Generally speaking, thena further practice of this aspect of the invention would be to employD_(x) Fe(CN)₆ (x is an integer greater than 0), rather than K₃ Fe(CN)₆,where it is desired to transport a drug, D+ species through the skinwithout cationic e.g., K⁺, competition.

In an analagous practice of this invention, negatively charged, anionicdrugs may be more efficiently delivered if an electrochemically activecomponent of the cathode is intentionally selected utilizing theprecepts of this invention.

An example of a sacrificial cathode electrochemically active material ofthis invention is chloridized silver. During device operation, the AgC1on the surface of a silver cathode is decomposed to give silver metaland chloride anion (AgC1+e⁻ →Ag+C1⁻). The chloride anion is free tomigrate, along with any anionic drug, into the body. In this respect,the Ag/AgC1 sacrificial cathode is less efficient than thesilver/chloride sacrificial anode in that chloride ion is produced andis delivered to the body. However, the beneficial aspects of the Ag/AgC1cathode include, (a) no hydrogen gas formation and (b) no hydroxylanions produced at the cathode.

One skilled in this art will recognize that a sacrificial cathode ofthis generic type generally comprises a metallic salt in contact with ametal cathode. Furthermore, device operation must result in thedecomposition of the metallic salt to form a metal in reduced form plusan anion. If both these conditions are met, in this practice of thepresent invention, anionic drugs are delivered with mitigation of pHchanges.

The use of a sacrificial cathode as herein described in conjunction withan anionic drug specifically selected so that the counterion will reactwith the anion being produced at the cathode to form an insoluble saltor neutral compound, provides an equivalent method for the control ofion transport as outlined for the anode and anodic reservoir.

Two examples of anionic drug (D⁻) which could be intentionally selectedfor use with an Ag/AgC1 cathode (these drugs would likely be dispersedor dissolved in the ion drug reservoir) are silver or copper salicylate.In this system, chloride ions formed at the cathode are free to reactwith silver or copper ions in the drug reservoir to form an insolublesalt thus allowing the negatively charged D⁻ anion to migrate into thebody without anionic competition.

In yet another method contemplated by the present invention to minimizethe formation of hydronium and hydroxide ions which consume current andreduce efficiencies, an intercalation-type cathode or anode is employed.Intercalation electrodes have the property of being capable of absorbingor desorbing alkali metal ions e.g., sodium and potassium, into theirstructure as the electrodes are oxidized or reduced. Examples of suchintercalation compounds would include sodium vanadate and sodiumtungstate. The use of intercalation-type cathode or anode materials isparticularly advantageous in that the formation of hydroxyl andhydronium ions is minimized along with a decline in the production ofhydrogen or oxygen gas.

It is to be recognized that electrodes comprising intercalation-typematerials may be used either on the anode or the cathode of theiontophoresis device and thus can deliver either positively ornegatively charged drugs. This can be illustrated for sodium tungstate,above, where the anodic reaction would be:

    Na.sub.1+x WO.sub.3 →Na.sup.+ +Na.sub.x WO.sub.3 +e.sup.-

For a cathodic reaction,

    Na.sup.+ +Na.sub.x WO.sub.3 +e.sup.- →Na.sub.1+x WO.sub.3.

For cathodic electrodes, incorporation of the alkali ion in the drugreservoir would be required. Preferably, this is accomplished bycompounding the anionic drug with the alkali metal ion as itscounterion. Other suitable intercalation type materials may includegraphite, beta alumina, organometallic compounds, transition metaldichalcogenides, prussian blue, polyaniline, polypyrrole, andpolyacetyline.

In another practive of the present invention, an intercalation-typeelectrode may be combined with a segmented reservoir to provide anelectrode which provides a more even current distribution and minimizesthe possibility of iontophoretic burns. FIG. 2 illustrates the side viewof such an electrode. The electrode 40 includes a conductive member 42which has on its surface an intercalation-type compound 44. Thiscompound is in contact with the drug containing gel 46 located inindividual compartments within the electrode, separated from each otherby walls or dividers 48, which prevent any substantial horizontal ionicmigration. FIG. 3 shows a bottom plan view of the electrode of FIG. 2,illustrating how the walls 48 divide the drug containing gel 46 intodifferent isolated compartments.

Intercalation-type compounds have two particular benefits in conjunctionwith the compartmentalized electrode. First, the rate of intercalationof ions into or out of the intercalation compound limits the currentflow and thus sets a maximum current density. The rate of intercalationinto or out of the electrode may be controlled by the type of polymerchosen for the drug reservoir and by the polymer morphology. Inaddition, after a predetermined number of ions have intercalated into orout of the intercalation compound in a particular area, the compoundpolarizes and becomes non-conductive in that area. In conjunction with asegmented electrode, this results in an automatic shut off of thecurrent flow through the compartment or compartments in that area, aftera predetermined amount of current flow.

The compartmentalized reservoir illustrated in FIGS. 2 and 3 is alsobelieved useful in conjunction with the combinations of currentdistributing members and ionic drugs described elsewhere in the presentapplication. Use of intercalation-type compounds in the absence of thecompartmentalized reservoir is also believed beneficial, as discussedabove. However, combining the two is believed to provide a significantadditional benefit which neither of the two elements individually canprovide.

In the absence of the compartmentalized electrode, use of anintercalation compound will still limit the total overall current flow,but horizontal migration of the ions through the gel could still resultin hot spots. Use of highly resistive gel for the drug reservoir wouldpermit limiting the overall current density, but at the expense ofbattery life. The compartmentalized reservoir alone would preventsubstantial horizontal migration of ions, but still would allow hotspots to form in individual compartments limited only by the resistanceof the reservoir gel. The combination of the intercalation-typeelectrode with the compartmentalized reservoir allows for the use of alow impedance polymer gel to prolong battery life while retaining theability to shut off areas of the electrode having unduly high currentdensity and thereby avoid iontophoretic burns.

A compartmentalized electrode designed similar to that illustrated inFIGS. 2 and 3 is particularly beneficial when combined with acompartmentalized sacrificial electrode. FIG. 4 shows a cross section ofsuch an electrode 50. The electrode 50 is provided with a multiplicityof individual electrode compartments, separated by compartment walls 52,which are impermeable to the passage of ions. Within each compartment islocated the drug reservoir gel 54, containing the ionic drug to bedelivered. The electrode is provided with a conductive currentdistribution member 56, which is adapted to be coupled to a source ofdirect electrical current via electrical connector 58. An insulativebacking 60 covers the current distribution member 56. Within eachcompartment is located a sacrificial electrode material. For example, insystems for delivery of a positive drug, this may be a silver mesh orfoil coating 62, applied to the current distribution member 56. It isimportant to note that the sacrificial electrode material 62 iscompartmentalized within the individual electrode compartments, and doesnot extend from one compartment to another.

An electrode fabricated in this fashion, has an effect similar to thataccomplished by the combination of intercalation compound with acompartmentalized electrode discussed above in conjunction with FIGS. 2and 3. In the case of an electrode adapted to deliver a positive drug,the electrode would operate as follows. The cationic drug (D⁺) iscompounded in its chloride form, within the individual gel compartments54. If one of the compartments experiences excessively high currentdrain, for example due to a breach or flaw in the skin in contact withthat cell, the current flowing through that compartment would convertthe sacrificial silver 62 to silver chloride more quickly than insurrounding cells. After the silver is completely converted to silverchloride, the current through that compartment would decreasesubstantially. This reduction in current flow is believed beneficial inavoiding iontophoretic burns, which might otherwise occur in the area ofthe breach or flaw in the skin.

In yet another practice of the instant invention in which the overallcoulombic efficiency of a given iontophoretic drug delivery device isenhanced, a metallic or amalgam electrode is employed optionally inconjunction with the addition of specific metal cations to the drugreservoir i.e., optionally with selection of a drug having a specificmetal cation. In this context, lead, mercury and mercury/cadmiumamalgams may be used in cathodic electrodes. In this practice of theinvention amalgam electrode is consumed during electrochemical dischargeof the device, and it reacts with a species intentionally made availableto the electrochemical oxidation/reduction product of the amalgam, e.g.,by adding a selected drug to the system such as in the drug reservoir.Thus, as in the context described above, the amalgam material hereindescribed is electrochemically reacted and undesired, highly mobile,charged species are consumed or removed. As with the intercalation-typecathode materials discussed above, the production of hydroxyl andhydronium ions during electrochemical discharge also is reduced. AgainpH stability is obtained, thus increasing the overall stability andefficiency of the drug delivery device.

In yet a further method for preventing the formation of hydroxyl ionsand hydrogen gas at the cathode is to intentionally select an anionicdrug whose counterion is an easily reducible metal such as silver orcopper. During operation of a device whose reservoir contains such ametal species, the metal ion is reduced to form the neutral metal andthe drug anion is free to migrate and carry charge toward the anode. Togeneralize, any reducible metal form of the anionic drug of interest maybe selected. The metal ion of the drug is reduced to a neutral species,i.e., it is plated out or effectively immobilized, and the drug anion isfree to migrate and carry charge toward the anode and into the body.

To this point, the present invention has been described in terms ofspecific selection of drugs or electrode materials so that the formationof water hydrolysis products (and the problems thereby created) areminimized. However, the present invention is not limited to electrodematerial/drug selections where electrode component is electrochemicallyoxidized or reduced during operation of the iontophoresis device. Themethod of this invention may be practiced with presently available"inert" electrodes if it is realized that their efficiency may besignificantly enhanced by the judicious, intentional selection of thedrug to be delivered.

Generally speaking, the use of inert electrodes to deliver drugs isaccomplished by selecting either the basic e.g., (OH⁻ or amine) or acid(H⁺) form of the drug to be incorporated into the reservoir, dependingupon whatever an anionic or cationic form of the drug is to bedelivered. Weak acid or weak base forms constitute a preferred class ofsuch drugs. For example, oxidation of water proceeds according to thehalf reaction, H₂ O→2H⁺ +1/20₂ +2e. Thus if the basic form of the drug(DOH) is incorporated into the reservoir, the reaction H⁺ +DOH→H₂ O+D⁺would occur, preferably in the drug reservoir. By this choice of drugform or drug precursor, hydronium ion is removed by conversion to theneutral species, water, and the concentration of D⁺ is increased. Inaddition, if a drug in its uncharged free-base form, D, wereincorporated into the drug reservoir, then the use of an "inert"electrode to produce hydronium ion, via oxidation of water, would leadto the formation of the charged drug species DH⁺ by the reaction D+H⁺→DH⁺. By this method, hydronium ion is removed by protonation of thedrug and the concentration of the desired species DH⁺ is increased. Aparticularly useful class of drugs which would behave in the fashiondescribed above are tertiary amines (R₃ N). Specific examples of suchdrugs are propranolol, nadolol, and metoprolol. Conversely, thereduction of water occurs according to the half reaction, H₂ O+e⁻ →OH⁻+1/2H₂. If it is desired to deliver an anionic drug (D⁻), the acid formof the drug (DH) should be incorporated into the reservoir. The reactionOH⁻ +HD→H₂ O+D⁻ would occur, thereby removing hydroxyl ions andincreasing D⁻ concentration. This application of the present inventionsuggests that if either a desired acid or basic form of a specificionically delivered drug is not available, synthesis for purposes ofenhanced iontophoretic drug delivery could be accomplished.

Two observations should be made regarding the description of the presentinvention in the previous paragraph. First, as described, an inertelectrode is intentionally employed to oxidize or reduce water. Theelectrochemically active component of the drug delivery device (e.g., astainless steel or platinum electrode component) in the iontophoreticdrug delivery process without itself being electrochemically changed orconsumed. Second, even though undesirable hydroxyl and hydronium ionsare formed, deletrious pH changes are minimized and hydronium ions andhydroxyl ions are converted to neutral water. In this practice of theinvention, the production of gaseous species i.e., H₂ and O₂, occurs andthus the sacrificial methods earlier described should be chosen if gasevolution is to be avoided.

Reference is now made to FIG. 1 included herewith. In the figure, thereis depicted, schematically, in cross section, a single substantially,circular electrode 10 which is intended for use in an iontophoretic drugdelivery device. It is to be understood that electrode 10 is but one ofthe two electrodes necessary to successful operation of an iontophoresisdevice and that the necessary source of electrical energy is also notdepicted herein.

Again referring to FIG. 1, electrode 10 comprises a support or housing12 which is generally "U" shaped and which is preferably flexible. In apreferred embodiment, support 12 is produced from self-supportingpolymeric foam. In this practice of the invention, perimeter surface 14of housing 12 would optionally have disposed thereon a skin-compatible,pressure-sensitive, biomedical adhesive 16 which is intended to hold theelectrode in place on the patient's skin during iontophoretic drugdelivery. The iontophoresis device may be held in place by other means,e.g., a strap, in which instance adhesive 16 would not be needed. Thusit is to be understood, as depicted, electrode 10 contemplates deliveryof drug generally toward the bottom of the page.

With further reference to FIG. 1, there is shown a drug reservoir 18which, in this practice of the invention, is a gel or gel matrix 21containing the ionic drug species 19 which is to be transdermallyintroduced across the skin barrier. In a preferred practice of theinvention, the self-supporting, skin-compatible gel matrix 21 for thedrug would contain sufficient drug 19 so that approximately a one molarsolution (applying the definition of a molarity from solvent-soluteinteractions) would result. Drug concentrations (in the reservoir) inthe range of 0.02M to 1.0M or more can be employed in the practice ofthis invention. In a preferred practice, the lower reservoir drugconcentration ranges (e.g., less than about 0.5 molar) can be used inthe efficient devices described herein. It should be noted that any of anumber of possible gel matrices may be employed, those being describedin the previously mentioned Webster patent comprising a particularlypreferred practice of this invention. Agar or polyvinylpyrolidone gelsalso are advantageously employed herein.

Also in FIG. 1, there is depicted an exterior connector 20 which in thisembodiment is a wire. Exterior connector 20 is in further electricalcontact with a current distribution member comprising a tab or plate 23in electrical contact with an optional screen 22. In this embodiment,the current distribution member would comprise silver. (The currentdistribution member need not be pure silver. An exterior layer of silveris all that is needed.) The silver screen is optionally included only toincrease the surface area of the current distribution member.

Thus, in operation, an external source of electrical energy (not shown)would be connected to exterior connector 20 which is, in turn,electrically connected to the silver current distribution member 22, 23.

It should be noted and with reference to the cathodic description of thesacrificial electrode described above that the silver currentdistribution member shown could be a silver/silver chloride cathode.Electrode 10, as depicted, would be placed in contact with a patient'sskin and pressed with sufficient firmness so that pressure sensitiveadhesive 16 would hold the drug reservoir 18 in contact therewith bymeans of flexible housing 12. Silver tab 20 would be electricallyconnected to a source of electrical energy, preferably a small battery.Utilization of a battery permits iontophoretic drug delivery withoutsubstantial interference with the normal activities of the patient.

It is within the contemplation of the present invention that stationaryelectrical supply sources be employed in which case it would likely benecessary for the patient to be substantially immobilized. Although notdepicted, a second indifferent or cooperating electrode would then beplaced in contact with the patient's skin at a site separate from butelectrically adjacent to the site on which electrode 10 has been placed.Upon connection to a source of electrical energy, migration of chargedspecies from reservoir 18 would occur. In this embodiment of theinvention, assuming the reservoir contains therein propranololhydrochloride or lithium chloride, the silver tab 23 and silver screen22 anode would be electrochemically consumed to produce silver ions asabove described. These silver ions would react immediately with chlorideions which are also present to produce a neutral, substantiallyinsoluble species. In this manner, enhanced delivery of propranolol orlithium would occur due to the fact that little hydrolysis occurs. Thesilver chloride precipitation reaction removes silver and chloride ionsfrom the reservoir, thus further enhancing efficiency.

Heretofore, the discussion has focused upon the use of iontophoresis totreat humans. Obviously, the invention herein disclosed could be usedwith animals and should not be limited to humans.

The instant invention will now be illustrated by the following exampleswhich should not be employed so as to limit the scope of this invention:

EXAMPLE I Description of the Experimental Procedure

In-vivo studies of iontophoretic drug delivery were run on New Zealandwhite rabbits. As indicated, the rabbits were in some studies sedated aswith pentobarbital, and others were merely constrained. The sedationstudies generally were conducted for a time period not exceeding 7 hourswhereas the "constrained" studies were run for time periods up to 30hours. Each rabbit was used in a particular study only once.

As is more completely described below, an iontophoretic device employingan electrode as shown and described in FIG. 1 was used to introducelithium, salicylate, propranolol or sodium chloride into the rabbits.The gel "reservoir" contained approximately a 1 molar concentration ofeach of the respective drugs. The device employed a silver anode and asilver/silver chloride cathode as described above.

The iontophoretic device was placed posteriorly on the rabbit, the hairhaving been clipped and removed with a dipilatory. The device was thenattached by means of an adhesive for the duration of the experiment.During the experimental procedure, blood samples were removed from thesubject rabbits. Where rabbits were anesthetized, blood samples wereremoved from their inferior vena cava by means of a catheter insertedinto the femoral vein. For the experiments employing constrained (ratherthan anesthetized) rabbits, blood samples were pulled from the heart bymeans of a catheter inserted into the marginal vein of the rabbit's ear.The samples thus withdrawn then were analyzed for the drug which wasiontophoretically introduced therein.

EXAMPLE II Description of the Data Treatment

Employing the experimental procedure described in Example I, the drugsof interest were iontophoretically introduced into rabbits. Bloodsamples were withdrawn as described and analyzed, the concentration ofthe respective drugs being plotted as a function of time. The data soobtained then was fit to the expression

    C=B .sup.(1-exp(-K i.sup.t))

where "C" is the concentration of drug in the rabbit's blood at aparticular time; "B" is the steady state drug concentration, i.e. thehighest concentration achieved when drug input and drug elimination arein equilibrium; K_(i) is the iontophoretic decay constant; and "t" istime. Tables 1, 2 and 3 indicate values of these parameters for a numberof runs (each "run" corresponding to numbers obtained from a givenrabbit, indicated by letter, on a given day, indicated by number). Thedrugs delivered in Tables 1, 2 and 3 were lithium ion, salicylate ionand propranolol ion, respectively.

                                      TABLE 1                                     __________________________________________________________________________    Lithium Drug Delivery Parameters                                                        Best Fit Parameters    Efficiency                                   Run  Current                                                                            B   K.sub.i                                                                           C.sub.o                                                                           K.sub.e                                                                             V.sub.d                                                                            E.sub.r                                                                          E.sub.c                                   No.  (mA) (mg/L)                                                                            (hr.sup.-1)                                                                       (mg/L)                                                                            (hr.sup.-1)                                                                         (liters)                                                                           (%)                                                                              (%)                                       __________________________________________________________________________    323A 10   3.0 0.66    0.16(a)                                                                             1.47(b)                                                                            27 24                                        323B 0    0.94                                                                              0.26    0.16(a)                                                                             1.47(b)                                           402C 20   5.2 0.31    0.16(a)                                                                             1.32(b)                                                                            21 20                                        403A 5    6.0 0.77    0.16(a)                                                                             1.37(b)                                                                            102                                                                              79                                        403B 10   4.4 0.84    0.16(a)                                                                             1.52(b)                                                                            41 36                                        403C 20   8.7 0.60    0.16(a)                                                                             1.62(b)                                                                            44 41                                        409A 30   16.7                                                                              0.31    0.16(a)                                                                             1.53(b)                                                                            53 51                                        409B 20   7.0 0.79    0.16(a)                                                                             1.56(b)                                                                            34 32                                        409C 10   6.6 0.29    0.16(a)                                                                             1.59(b)                                                                            65 57                                        425A 0    --  --  --  0.12                                                    425C 0    --  --  1.41                                                                              0.09                                                    510A 1    0.3 --      0.16(a)                                                                             1.63(b)                                                                            30                                           510B 5    1.0 0.51    0.16(a)                                                                             1.89(b)                                                                            23                                           510C 5    4.0 0.16    0.16(a)                                                                             1.82(b)                                                                            90 70                                        611A 0    3.0 0.82                                                                              2.61                                                                              0.14  1.25 .sup.                                        611B 0.5  0.27                                                                              0.19                                                                              1.97                                                                              0.19  1.66 .sup.                                                                         66 17                                        611C 2    1.6 0.27                                                                              2.17                                                                              0.16  1.51 .sup.                                                                         75 44                                        619F 0.5  3.0 1.72    0.16(a)                                                                             1.20(b)                                                                            445                                                                              116                                       619G 0.5  2.9 1.06                                                                              2.62                                                                              0.27  1.25 .sup.                                                                         766                                                                              200                                       619H 0    2.1 1.13    0.16(a)                                                                             1.40(b)                                           619I.sup.                                                                          1    0.71                                                                              0.20    0.16(a)                                                                             1.35(b)                                                                            59 24                                        Average       0.54    0.16            43(c)                                   S.D.          ±0.32                                                                              +0.06         ±20                                    __________________________________________________________________________     (a)assumed value based on average K.sub.e.                                    (b)assumed value based on 0.49 × body weight in kg.                     (c)average for currents greater than or equal to 1 mA.                   

                                      TABLE 2                                     __________________________________________________________________________    Salicylate Drug Delivery Parameters                                                     Best Fit Parameters    Efficiency                                   Run  Current                                                                            B   K.sub.i                                                                           C.sub.o                                                                           K.sub.e                                                                             V.sub.d                                                                            E.sub.r                                                                          E.sub.c                                   No.  (mA) (mg/L)                                                                            (hr.sup.-1)                                                                       (mg/L)                                                                            (hr.sup.-1)                                                                         (liters)                                                                           (%)                                                                              (%)                                       __________________________________________________________________________    323A 10   157 0.36    0.25(a)                                                                             0.72(b)                                                                            55 47                                        323B 0    60.4                                                                              0.53    0.25(a)                                                                             0.72(b)                                           402C 20   130 2.35    0.25(a)                                                                             0.65(b)                                                                            21 19                                        403A 5    182 0.91    0.25(a)                                                                             0.68(b)                                                                            121                                                                              90                                        403B 10   96.8                                                                              1.23    0.25(a)                                                                             0.75(b)                                                                            35 30                                        403C 20   173 1.47    0.25(a)                                                                             0.80(b)                                                                            34 31                                        409A 30   204 0.93    0.25(a)                                                                             0.76(b)                                                                            25 24                                        409B 20   109 3.43    0.25(a)                                                                             0.77(b)                                                                            21 19                                        409C 10   85.6                                                                              0.98    0.25(a)                                                                             0.78(b)                                                                            33 28                                        425A 0                0.46                                                    425C 0            320 0.18  0.63                                              510A 1    4           0.25(a)                                                                             0.80(b)                                                                            16                                           510B 5    17.1                                                                              0.86    0.25(a)                                                                             0.93(b)                                                                            16                                           510C 5    37.6                                                                              0.36    0.25(a)                                                                             0.90(b)                                                                            33 25                                        611A 0    45.0                                                                              0.16                                                                              275 0.31  0.62                                              611B 0.5  32.3                                                                              0.09                                                                              207 0.23  0.83 241                                                                              55                                        611C 2    73.6                                                                              0.32                                                                              187 0.22  0.92 146                                                                              79                                        619F 0.5  40          0.25(a)                                                                             0.59(a)                                                                            231                                                                              52                                        619G 0.5  46.0                                                                              1.05    0.30  0.54 291                                                                              66                                        619H 0    12          0.25(a)                                                                             0.68(b)                                           619I.sup.                                                                          1    37.9                                                                              0.94    0.25(a)                                                                             0.66(b)                                                                            122                                                                              45                                        Average       0.73    0.25            28(c)                                   S.D.          ±0.42                                                                              ±0.06      ±9                                     __________________________________________________________________________     (a)assumed value based on average                                             (b)assumed value based on 0.24 × body weight in kg.                     (c)average for currents ≧5 mA                                     

                                      TABLE 3                                     __________________________________________________________________________    Propranolol Drug Delivery Parameters                                                    Best Fit Parameters    Efficiency                                   Run  Current                                                                            B   K.sub.i                                                                           C.sub.o                                                                           K.sub.e                                                                             V.sub.d                                                                            E.sub.r                                                                          E.sub.c                                   No.  (mA) (mg/L)                                                                            (hr.sup.-1)                                                                       (mg/L)                                                                            (hr.sup.-1)                                                                         (liters)                                                                           (%)                                                                              (%)                                       __________________________________________________________________________    613D 0.5  0.13                                                                              0.30                                                                              0.08                                                                              0.40  21.2 23 16                                        613E 2    0.11                                                                              0.24                                                                              0.08                                                                              0.40  22.3  5 3                                         627J 0    0       0.17                                                                              0.44  10.7 -- --                                        627K 0.5  0.08                                                                              0.16                                                                              0.33                                                                              0.40  5.3   3 0                                         627L 1    0.24                                                                              0.43                                                                              0.15                                                                              0.30  11.7  9 6                                         705N 0.5  0.05                                                                              0.35                                                                              0.19                                                                              0.61  9.2   6 0                                         705O 0.5  0.23                                                                              0.30                                                                              --    0.39(a)                                                                           11.4(b)                                                                            21 14                                        705P 1.0  0.17                                                                              0.26                                                                              0.08                                                                              0.47  22.3 18 15                                        705Q 1.0  0.15                                                                              0.28                                                                              --    0.39(a)                                                                           9.8(b)                                                                              6 3                                         724R 0    0.35                                                                              0.14                                                                              0.24                                                                              0.39  7.2  -- --                                        724S 0.5  0.13                                                                              0.30                                                                              --    0.39(a)                                                                           15.1(b)                                                                            16 9                                         724T 0    0.19                                                                              0.25                                                                              0.21                                                                              0.46  8.5  -- --                                        724U 1.0  0.25                                                                              0.32                                                                              0.17                                                                              0.22  10.6  6 3                                         801V 0.5  0.11                                                                              0.56                                                                              0.08                                                                              0.24  21.7 12 5                                         801W 1.0  0.24                                                                              0.18                                                                              --    0.39(a)                                                                           10.2(b)                                                                            10 7                                         810X 0    0.05                                                                              0.63                                                                              --    0.39(a)                                                                           10.9(b)                                                                            -- --                                        801Y 0    0.06                                                                              0.50                                                                              0.16                                                                              0.33  10.9 -- --                                        Average       0.32    0.39            6.8                                     S.D.          ±0.14                                                                              ±0.11      ±5.6                                   __________________________________________________________________________     (a)value based on average K.sub.e                                             (b)value based on 5.3 × body weight in kg.                         

EXAMPLE III

For some of the rabbits tested, a known amount of a given drug wasadministered intravenously and the consumption of the drug by the animalwas monitored as a function of time. From these data, values for thedrug elimination decay constant (K_(e)) and the initial drugconcentration (C_(o)) were determined by plotting the natural logarithmof concentration (1nC) versus time. Once the value of C_(o) and theintravenous dosage has been determined, the volume of distribution(V_(d)) was calculated using the expression

    V.sub.d =Dose/Co

Tables 1, 2 and 3 list the values of C_(o), K_(e) and V_(d) as they weredetermined or estimated for each run.

EXAMPLE IV

The parameters listed in Tables 1, 2 and 3 can be used to estimate theefficiency of drug delivery. An estimate of the steady-state drugdelivery rate (R_(d)) can be made by multiplying the plateau drugconcentration (B) by the volume of distribution (V_(d)) and the drugelimination decay constant (K_(e)), that is,

    R.sub.d (mg/hr)=B V.sub.d K.sub.e                          (1)

The maximum amount of drug iontophoretically delivered per unit time(R_(t)) can be calculated from the current used during the experiment,that is, ##EQU1## where M is the molecular weight of the drug ion, I isthe current in milliamps and F is Faraday's constant. The efficiency ofdrug delivery (E_(r)) can be estimated from the ratio R_(d) /R_(t)according to the expression ##EQU2## Tables 1, 2 and 3 list theefficiencies estimated from the in-vivo rabbit data for each experiment.

It is to be noted that for some of the runs, the value of E_(r) exceeded100%. This is possible since R_(d) includes a contribution due topassive diffusion of the drug through the skin, therefore the ratioR_(d) /R_(t) can exceed unity.

EXAMPLE V

Also listed in Tables 1, 2 and 3 is the true efficiency of drug delivery(E_(c)) for each experiment which was calculated by subtracting thepassive drug delivery rate (R_(p)) from the total drug delivery rate(R_(d)), that is, ##EQU3## The method used to determine the passivediffusion rate for each drug is discussed in Example VI below.

EXAMPLE VI

It was found that total in-vivo drug delivery data, as defined inequation (1) of Example IV, was the sum of two contributions, onepassive and the other iontophoretic. Thus, it was found that the rate ofdrug delivery (R_(d)) could be expressed as

    R.sub.d =R.sub.p +R.sub.i                                  (4)

where R_(p) is the rate of passive drug delivery and R_(i) is the rateof iontophoretic drug delivery. The rate of passive delivery depends onthe area of contact and the drug concentration of the drug reservoir.The rate of iontophoretic delivery is directly proportional to thecurrent used in the experiment, that is,

    R.sub.i =AE.sub.c I

where E_(c) is the efficiency of drug delivery, I is the current and Ais a proportionally constant whose value is determined by the molecularweight of the drug.

Substitution of the above expression for R_(i) into Equation (4) yields

    R.sub.d =R.sub.p +AE.sub.c I                               (5)

By using the data presented in Tables 1, 2 and 3, a plot of R_(d) versuscurrent can be made for each drug. From the form of Equation (5), it isreadily seen that the intercept of a linear least-squares fit of suchplots will yield the passive drug diffusion rate (R_(p)) and the slopecan be used to calculate the efficiency of drug delivery (E_(c)).

EXAMPLE VII

From the data obtained as described above, a plot of R_(d) versuscurrent for lithium chloride, sodium salicylate and propranololhydrochloride was made and a best linear fit obtained. The rates ofpassive drug delivery for each of these drugs then is determined by theintercept of this "fit". Values of this intercept are listed in Table 4.Also listed in Table 4 is the equivalent current for each drug. Theequivalent current for a given drug is the current at which half of thedrug delivery would occur via passive diffusion and half would occuriontophoretically.

The slopes of the best linear fit of R_(d) versus current describedabove were used to estimate the efficiency (E_(c)) for in-vivo drugdelivery. Table 5 compares the efficiency estimated from the in-vivoexperiments to those determined from in-vitro drug delivery throughexcised rabbit skin and through polyvinyl alcohol (PVA) membrane into a0.1M sodium chloride solution. The in-vitro drug delivery measurementswere taken in accordance with using a Franz diffusion cell commerciallyavailable from the Crown Glass Company, Somerville, N.J., U.S.A.

The efficiency of in-vitro drug delivery through a PVA membrane is anindication of the relative mobilities of lithium and propranolol withrespect to chloride ion, and salicylate with respect to sodium ion. Theefficiency of drug transport through a PVA probably represents an upperlimit for the efficiency for the gels, electrodes and drugconcentrations likely to be used in the in-vivo experiments.

The data presented in Table 4 indicates that lithium and propranololwere transported approximately equally efficiently through excised andviable rabbit skin. Further the data indicates the salicylate was moreeffectively delivered through viable tissue than through excised skin.

                  TABLE 4                                                         ______________________________________                                        Passive Diffusion Rate                                                                                Equivalent                                            Drug          R.sub.p (mg/hr)                                                                         Current (mA)                                          ______________________________________                                        Lithium       0.37      1.42                                                  Salicylate    8.8       1.71                                                  Propranolol   0.33      0.034                                                 ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        In-Vivo and In-Vitro Coulombic Efficiencies                                                    In-Vitro                                                     Drug       In-Vivo     Rabbit Skin                                                                             PVA Gel*                                     ______________________________________                                        Lithium    35%         33%       30%                                          Salicylate 19%         6%        30%                                          Propranolol                                                                               5%         5%        11%                                          ______________________________________                                         *polyvinyl alcohol                                                       

To summarize, while there does appear to be a fair amount of scatter inthe in-vivo data, we have found that the methods described hereinprovide a fairly reproducible method for determining efficiencies andpassive drug delivery rates for in-vivo studies. The efficiencies socalculated appear to be in substantial agreement with similarefficiencies computed from in-vitro experiments.

EXAMPLE VIII

A number of anode/cathode drug combinations and drug concentrations wereevaluated with respect to their minimization of the production ofundesired species. In particular, drug reservoir pH changes weremeasured, from which hydronium ion delivery rates were computed. Thedrug passed through a PVA membrane and was delivered into a 0.06M Na C1.Further, using the mathematical treatment described above, drug deliveryefficiencies were determined. Experimental conditions and efficiencieswere measured for delivery of lithium ion, potassium ion and salicylateion as indicated in Tables 6, 7, 8 and 9.

A number of observations may be made about the systems tested. Systemsnumbered 1-6 of Table 6 are basically prior art systems.

Undesirable water hydrolysis products are produced and thus pH is shownto change fairly substantially as in "pH" column for systems 1, 2 and 3in Table 7, 1 and 2 of Table 8 and 1 of Table 9.

An evidenced in Tables 7, 8 and 9 hydronium delivery rates weregenerally higher, and drug delivery efficiencies were generally lowerfor prior art systems versus systems employing the present invention.For example, systems numbered 1, 2 and 3 in Table 7 may be compared withsystems numbered 4-9 in Table 7. Similarly systems 1 and 2 in Table 8should be compared with 3-6 in Table 8 and system 1 in Table 9 with 2-8in Table 9.

To summarize, in conjunction with the teaching above, a broadly-based,flexible approach to solving the problem of inefficiency/instability iniontophoretic drug delivery is disclosed. While this disclosure hasfocused upon two cationic and one anionic drug, it will be appreciatedthat this invention is broadly applicable to the iontophoresis art. Theattached claims should be so broadly construed.

                                      TABLE 6                                     __________________________________________________________________________    Summary of Experimental Conditions                                                    Reservoir                                                                     Concen-                                                                       tration                                                                             Electrode                                                       Drug    (M)   Material                                                                            Electrode Reaction                                                                          Neutralization Reaction                     __________________________________________________________________________     1.                                                                             LiCl  0.06  Platinum                                                                            H.sub.2 O → 2H.sup.+ + 1/2O.sub.2                                                    None.sup.-                                   2.                                                                             LiNO.sub.3                                                                          0.06  Platinum                                                                                 "         "                                           3.                                                                             LiCl  0.06  S. Steel                                                                                 "         "                                           4.                                                                             KCl   0.06  Platinum                                                                                 "         "                                           5.                                                                             K.sub.3 Fe(CN).sub.6                                                                0.02  Platinum                                                                                 "         "                                           6.                                                                             NaSal 0.06  Platinum                                                                            H.sub.2 O + e.sup.- → OH.sup.- + 1/2                                                  "sub.2                                      7.                                                                             LiNO.sub.3                                                                          0.06  Silver                                                                              Ag → Ag.sup.+ + e.sup.-                                                              None                                         8.                                                                             LiNO.sub.3                                                                          0.06  Copper                                                                              Cu → Cu.sup.++ + e.sup.-                                                              "                                           9.                                                                             KNO.sub.3                                                                           0.06  Silver                                                                              Ag → Ag.sup.+ + e.sup.-                                                               "                                          10.                                                                             NaSal 0.06  Ag/AgCl                                                                             AgCl + e.sup.- → Ag + Cl.sup.-                                                        "                                            HSal  Solid Ag/AgCl                                                                             AgCl + e.sup.- → Ag + Cl.sup.-                                                        "                                            Cu(Sal).sub.2                                                                       0.05  Silver                                                                              Cu.sup.++ + 2e.sup.- → Cu                                                             "                                            AgSal 0.04  Silver                                                                              Ag.sup.+ + e.sup.- → Ag                                                               "                                            AgSal Solid Platinum                                                                            Ag.sup.+ + e.sup.- → Ag                                                               "                                            LiCl  0.06  Silver                                                                              Ag → Ag.sup.+ + e.sup.-                                                              Ag.sup.+ + Cl.sup.- → AgCl             Li.sub.2 CO.sub.3                                                                   0.03  Silver                                                                              Ag → Ag.sup.+ + e.sup.-                                                              2Ag.sup.+ + CO.sub.3 → Ag.sub.2                                        CO.sub.3                                      LiCl  0.06  Copper                                                                              Cu → Cu.sup.+ +  e.sup.-                                                             Cu.sup.+ + Cl.sup.- → CuCl             LiOH  0.06  Platinum                                                                            H.sub.2 O → 2H.sup.+ + 1/2O.sub.2                                                    H.sup.+ + OH.sup.- → H.sub.2 O         KCl   0.06  Silver                                                                              Ag → Ag.sup.+ + e.sup.-                                                              Ag.sup.+ + Cl.sup.- → AgCl           20.                                                                             K.sub.3 Fe(CN).sub.6                                                                0.02  Silver                                                                              Ag → Ag.sup.+ + e.sup.-                                                              3Ag.sup.+ + Fe(CN).sub.6.sup.3-                                               → Ag.sub.3 Fe(CN).sub.6                K.sub.3 Fe(CN).sub.6                                                                0.02  Copper                                                                              Cu → Cu.sup.+ + e.sup.-                                                              3Cu.sup.+ + Fe(CN).sub.6.sup.3-                                               → Cu.sub.3 Fe(CN).sub.6                AgSal Solid Ag/AgCl                                                                             AgCl + e.sup.- → Ag + Cl.sup.-                                                       Cl.sup.- + AgSal → AgCl +                                              Sal.sup.-                                     HSal  Solid Platinum                                                                            H.sub.2 O + e.sup.-  → OH.sup.- + 1/2H.sub.2                                         OH.sup.- + HSal → H.sub.2 O +                                          Sal.sup.-                                   __________________________________________________________________________

                  TABLE 7*                                                        ______________________________________                                        Comparison of Lithium Drug Delivery Systems                                                      Hydronium                                                             % Drug  Delivery  pH                                                       Anode    Delivery  Rate    Initial                                                                             After                                Drug    Material Efficiency                                                                              (moles/hr)                                                                            Value 6 hrs                                ______________________________________                                        1.  LiCl    Platinum 20.2    3.2 × 10.sup.-6                                                                 5.9   2.6                                2.  LiNO.sub.3                                                                            Platinum 22.8    2.0 × 10.sup.-6                                                                 7.2   2.5                                3.  LiCl    S. Steel 29.1    1.8 × 10.sup.-7                                                                 6.2   3.7                                4.  LiNO.sub.3                                                                            Silver   28.5    5.5 × 10.sup.-8                                                                 5.9   4.3                                5.  LiNO.sub.3                                                                            Copper   25.0    <10.sup.-9                                                                            5.9   5.6                                6.  LiCl    Silver   36.7    <10.sup.-9                                                                            6.5   6.2                                7.  LiCl    Copper   30.2    <10.sup.-9                                                                            6.1   5.5                                8.  Li.sub.2 CO.sub.3                                                                     Silver   29.5    <10.sup.-9                                                                            10.6  10.2                               9.  LiOH    Platinum 41.6    1.5 × 10.sup.-8                                                                 11.5  11.3                               ______________________________________                                         *All results obtained at a current of 1 mA.                              

                                      TABLE 8                                     __________________________________________________________________________    Comparison of Potassium Drug Delivery Systems*                                                % Drug                                                                              Hydronium                                                                             pH                                                         Anode                                                                              Delivery                                                                            Delivery                                                                              Initial                                                                            After                                      Drug       Material                                                                           Efficiency                                                                          Rate (moles/hr)                                                                       Value                                                                              6 hrs                                      __________________________________________________________________________    1. KCl     Platinum                                                                           33.7  1.4 × 10.sup.-6                                                                 5.8  2.7                                        2. K.sub.3 Fe(CN).sub.6                                                                  Platinum                                                                           28.6  2.1 × 10.sup.-6                                                                 6.4  2.6                                        3. KNO.sub.3                                                                             Silver                                                                             36.2  5.4 × 10.sup.-9                                                                 5.8  4.3                                        4. KCl     Silver                                                                             39.1  <10.sup.-9                                                                            6.0  5.6                                        5. K.sub.3 Fe(CN).sub.6                                                                  Silver                                                                             34.3  1.0 × 10.sup.-8                                                                 6.4  5.9                                        6. K.sub.3 Fe(CN).sub.6                                                                  Copper                                                                             33.8  .sup. 8.9 × 10.sup.-10                                                          7.2  4.9                                        __________________________________________________________________________     *All results obtained at a current of 1 mA.                              

                                      TABLE 9                                     __________________________________________________________________________    Comparison of Salicylate Drug Delivery Systems*                                                               pH                                                         % Drug Delivery                                                                        Hydroxyl Delivery                                                                       Initial                                                                           After                                     Drug    Material                                                                           Efficiency                                                                             Rate (moles/hr)                                                                         Value                                                                             6 hrs                                     __________________________________________________________________________    1. NaSal                                                                              Platinum                                                                           25.9     4.6 × 10.sup.-6                                                                   6.0 11.5                                      2. NaSal                                                                              Ag/AgCl                                                                            27.8     <10.sup.-9                                                                              6.5 5.6                                       3. HSal Ag/AgCl                                                                            20.9     <10.sup.-9                                                                              3.5 2.9                                       4. Cu(Sal).sub.2                                                                      Silver                                                                             28.3     <10.sup.-9                                                                              4.5 4.5                                       5. AgSal                                                                              Silver                                                                             28.2     1.0 × 10.sup.-7                                                                   8.6 8.7                                       6. AgSal                                                                              Platinum                                                                           24.9     3.3 × 10.sup.-8                                                                   5.2 8.1                                       7. AgSal                                                                              Ag/AgCl                                                                            25.0     .sup. 2.9 × 10.sup.-10                                                            5.2 5.4                                       8. HSal Platinum                                                                           28.1     .sup. 8.6 × 10.sup.-11                                                            2.8 3.4                                       __________________________________________________________________________     *All results obtained at a current of 1 mA.                              

We claim:
 1. A method of increasing the efficiency of an iontophoreticelectrode for delivery of an ionic drug having a positive charge byminimizing delivery of mobile cations other than said ionic drug,hereafter referred to as competing cations, comprising the followingsteps:forming a reservoir containing said ionic drug with a negativelycharged counter-ion, said reservoir being substantially free of cationswhich can compete with the drug ions for carrying charge from thereservoir to a body surface, the reservoir also being permeable to saidionic drug; applying to said reservoir an electrically conductive membercomprising a sacrificial material readily oxidizable when saidconductive member is in contact with said reservoir and a positivevoltage is applied to said conductive member, said material whenoxidized readily combining with said counter-ion to form a compoundwhich is substantially immobile within said reservoir during theapplication of said positive voltage; placing said reservoir containingsaid ionic drug in drug transmitting relation to the body surface of apatient; and while said reservoir is in drug transmitting relation tothe body surface of said patient and said conductive member is appliedto said reservoir, applying a positive voltage to said conductive memberto oxidize said material and to drive said ionic drug through the bodysurface of said patient, whereby said ionic drug is driven through saidbody surface substantially without cationic competition.
 2. A methodaccording to claim 1 wherein said material is silver and wherein saidcounter-ion is chloride.
 3. A method according to claim 1 wherein saidmaterial is silver and wherein said counter-ion is ferrocyanide.
 4. Amethod according to claim 1 wherein said material is copper and saidcounter-ion is ferrocyanide.
 5. A method according to claim 1 or claim 2wherein said ionic drug comprises ionic lithium.
 6. A method accordingto claim 1 or claim 2 wherein said ionic drug comprises ionic potassium.7. A method according to claim 1 or claim 2 wherein said step ofincorporating said ionic drug comprises incorporating propranalol withsaid negatively charged counter-ion.
 8. A method according to claim 7wherein said propranalol is provided in the form of propranalolhydrochloride.
 9. A method of increasing efficiency of delivery in aniontophoretic electrode for delivery of an ionic drug having a positivecharge by minimizing delivery of competing cations, comprising the stepsof:applying an electrically conductive member to a reservoir containingsaid ionic drug compounded with a negatively charged counter-ion, saidreservoir being substantially free of cations which can compete with thedrug ions for carrying charge from the reservoir to a body surface, thereservoir also being permeable to said ionic drug, said electricallyconductive member comprising a sacrificial material readily oxidizablewhen said conductive member is in contact with said reservoir and apositive voltage is applied to said conductive member, said materialwhen oxidized readily combining with said counter-ion and which when socombined forms a compound which is substantially immobile within saidreservoir during the application of said positive voltage; placing saidreservoir in drug transmitting relation to the body surface of thepatient; and while said reservoir is in drug transmitting relation tothe body surface of said patient and said conductive member is appliedto said reservoir, applying a voltage to said conductive member tooxidize said material and to drive said ionic drug through the bodysurface of said patient substantially free of cationic competition. 10.A method according to claim 1 wherein said material is tin and saidcounterion is phosphate.
 11. A method according to claim 1 wherein saidmaterial is zinc and said counterion is phosphate.
 12. A methodaccording to claim 1 wherein said material is zinc and said counterionis oxalate.
 13. A method according to claim 1 wherein said material iscopper and said counterion is citrate.
 14. A method of increasing theefficiency of delivery of an ionic drug having a negative charge from aniontophoretic electrode by minimizing the delivery of mobile anionsother than said ionic drug, comprising the follow steps:forming areservoir containing the drug with a positively charged counter-ion,said reservoir being substantially free of anions which can compete withthe drug ions for carrying charge from the reservoir to a body surface,the reservoir also being permeable to said ionic drug; applying to saidreservoir an electrically conductive member comprising a sacrificialmaterial which is readily reducible when said conductive member is incontact with said reservoir and a negative voltage is applied to saidconductive member, said material when reduced forming an anion which isreadily combined with said counter-ion to form a compound which isimmobile within said reservoir during the application of said negativevoltage; placing said reservoir in drug transmitting relation to thebody surface of a patient; and while said reservoir is in drugtransmitting relation to the body surface of said patient and saidconductive member is applied to said reservoir, applying a negativevoltage to said conductive member to reduce said material and to drivesaid ionic drug through the body surface of said patient, whereby saidionic drug is driven through said body surface substantially withoutanionic competition.
 15. A method of increasing efficiency of deliveryof an ionic drug having a negative charge from an iontophoreticelectrode by minimizing delivery of competing anions, comprising thesteps of:applying an electrically conductive member to a reservoircontaining said ionic drug compounded with a positively chargedcounter-ion, said reservoir being substantially free of anions which cancompete with the drug ions for carrying charge from the reservoir to abody surface, said reservoir also being permeable to said ionic drug,said electrically conductive member comprising a sacrificial materialwhich is readily reducible when said conductive member is in contactwith said reservoir and a negative voltage is applied to said conductivemember, said material when reduced forming an anion which is readilycombined with said counter-ion and which when so combined forms acompound which is substantially immobile within said reservoir duringthe application of said negative voltage; placing said reservoir in drugtransmitting relation to the body surface of the patient; and while saidreservoir is in drug transmitting relation to the body surface of saidpatient and said conductive member is applied to said reservoir,applying a voltage to said conductive member to reduce said material andto drive said ionic drug through the body surface of said patientsubstantially free of anionic competition.
 16. The method of claim 14 or15, wherein the sacrificial material comprises chloridized silver andthe anion which is formed when the material is reduced compriseschloride anion.
 17. The method of claim 14 or 15, wherein thecounter-ion of the drug comprises a reducible metal.
 18. The method ofclaim 17, wherein the reducible metal is selected from the groupconsisting of silver and copper.
 19. The method of claim 14 or 15,wherein the ionic drug comprises salicylate.
 20. The method of claim 1,9, 14 or 15 wherein the body surface is selected from the groupconsisting of skin and mucosal membrane.